Analysis of sex-specific lipid metabolism in P. falciparum gametocytes points to importance of sphingomyelin for gametocytogenesis

Male and female Plasmodium falciparum gametocytes are the parasite lifecycle stage responsible for transmission of malaria from the human host to mosquito vector. Not only are gametocytes able to survive in radically different host environments, but they are also precursors for male and female gametes that reproduce sexually soon after ingestion by the mosquito. Here we investigate the sex-specific lipid metabolism of gametocytes within their host red blood cell and poised for ingestion by the mosquito vector and subsequent sexual reproduction. Comparison of the male and female lipidome identifies cholesteryl esters and dihydrosphingomyelin enrichment in female gametocytes. Chemical inhibition of each of these lipid types in mature gametocytes suggests dihydrosphingomyelin synthesis but not cholesteryl ester synthesis is important for sex-specific gametocyte viability. Genetic disruption of each of the two sphingomyelin synthase gene points towards sphingomyelin synthesis contributing to gametocytogenesis. This study shows that gametocytes are not only distinct from asexual stages, but that the lipid composition is also vastly different between male and female gametocytes, reflecting the different cellular roles these stages play. Together our results highlight the sex-specific nature of gametocyte lipid metabolism that has the potential to be targeted to block malaria transmission.